Our group used functional neuroimaging to determine local neuronal activity in patients with schizophrenia and other neuropsychiatric disorders during performance of working memory and abstract reasoning tasks as well as during performance of matched sensorimotor control tests and other contrast tasks. By using a 2-back version of an N-back continuous working memory task, we have re-confirmed previous findings derived from the Wisconsin Card Sorting Test (WCST) of dysfunction of prefrontal cortex. As in previous studies, the aberrant activation pattern appears to occur even in patients who perform relatively well on the task. We also examined changes in cognitive activation across several time points during a medication-free period in individual patients. This determined the relationship between the physiological changes and concomitant changes in symptoms and cognitive performance. Further analyses of the time course of these changes are ongoing. We have also explored the functional connectivity among various nodes of the working memory system. This has shown that more than half the intergroup variance (across controls and patients) was explained by a single pattern showing inferotemporal-hippocampal-cereballar loading for patients versus dorsolateral-prefrontal-cingulate activity for controls. Expression of this pattern perfectly separated all patient scans from the control group, a finding prospectively validated in two new data sets, suggesting that it may be a trait marker. We have further demonstrated that an important component of this pattern lies in specific abnormality in the functional relationship between the dorsolateral prefrontal cortex (DLPFC) and the hippocampus. We have also shown that even when patients with schizophrenia are compared with young normal subjects with equally poor performance, they still have diminished prefrontal cortical response while performing tasks with a strong working memory component. We have now initiated a number of cross-modal neuroimaging studies in schizophrenia. We previously found that prefrontal N-acetylaspartate (NAA) magnetic resonance spectroscopy signal predicts impaired WCST regional cerebral blood flow (rCBF) activation not only in the prefrontal cortices of our patients, but also in other nodes in the working memory system. This relationship was found in patients, but not in control subjects, and not with NAA in other brain regions. Additionally, we used PET to determine whether and how abnormal striatal presynaptic dopaminergic neurotransmission and disturbed prefrontal cortical function interact in schizophrenia. We determined both prefrontal activity (measured with rCBF) during the WCST and presynaptic dopaminergic function (measured with 18F-DOPA) in patients withdrawn from medication and matched normal controls. Striatal FDOPA uptake in patients was significantly higher than in normal controls, while WCST-related activity in prefrontal cortex was decreased. Most importantly, in patients there was a highly significant negative correlation between task-related prefrontal and striatal dopamine uptake which was absent in controls. This study provided a mechanistic explanation for the coexistence of two key pathophysiological hallmarks of schizophrenia. This year we reviewed the psychopathological manifestations impacting real-world functioning of affected individuals, most arguably, executive impairment, for which there are numerous disrupted component processes, and a very complex dysfunctional neural architecture. Postmortem and neuroimaging studies continue to show alterations in many interacting signaling pathways. There is also an evolving understanding that genetic risk factors give multiple entry points to illness liability. Given all this, we take a systems-level approach to executive dysfunction in schizophrenia by identifying 1) key brain regions that show changes in schizophrenia patients and are also important in cognitive neural circuitry, 2) relevant functional interactions and 3) examined links between risk genes and executive circuit abnormalities observed with neuroimaging. We studied the effect of the COMT (catechol-O-methyltransferase) val158met genotype with relation to resting regional cerebral blood flow (rCBF). The COMT gene, with the high-activity val allele, is weakly associated with risk for schizophrenia, which results in deficits in prefrontal functioning and poor working memory performance in healthy controls and patients with schizophrenia. The low-activity met allele is associated with anxiety and pain and with increased limbic reactivity while viewing aversive images. The effect of the COMT polymorphism is consistent with schizophrenia, during engagement of cognitive tasks. However, task-independent (resting) effects of this polymorphism in schizophrenia have not been characterized. There is mounting evidence for aberrant prefrontal and limbic brain function in schizophrenia during rest, and a lack of data regarding COMT effects on schizophrenia patients at rest. In medication-free patients, we identified the relationship between COMT genotype and resting rCBF in brain structures associated with schizophrenia pathophysiology and where COMT effects have been shown during executive and affective tasks. Our data suggests in schizophrenia at rest, brain structures important for executive and affective processing show activity that is differentially predicted by COMT val or met allele in an opposing manner. Thus, providing evidence that in schizophrenia, COMT genotype shows effects even in the resting state.